14-3-3β and γ differentially regulate peroxisome proliferator activated receptor γ₂ transactivation and hepatic lipid metabolism

Peroxisome proliferator activated receptor (PPAR) γ₂ plays important roles in glucose and lipid metabolism in hepatocytes. PPARγ₂ is involved in metabolic disorders, including obesity, diabetes, and fatty liver disease. Although the 14-3-3 proteins participate in a variety of cell signal pathways, the roles of the 14-3-3 proteins in regulating PPARγ₂ transactivation and hepatic lipid metabolism are unknown. We identified 14-3-3β and γ as PPARγ₂ transcriptional regulators. We found that 14-3-3β and γ competitively interacted with the phosphorylated Ser273 of PPARγ₂, which is important for regulating glucose and lipid metabolism. 14-3-3β increased the transcriptional activity of PPARγ₂ and enhanced the expression levels of PPARγ₂ target genes involved in lipogenesis and lipid transport. In contrast, 14-3-3γ decreased PPARγ₂ transactivation and reduced the expression levels of PPARγ₂ target genes. A high concentration of free fatty acids increased PPARγ₂ expression and lipid accumulation. 14-3-3β enhanced hepatic lipogenesis, which is a major symptom of non-alcoholic fatty liver disease. However, 14-3-3γ suppressed hepatic lipid accumulation in the presence of high free fatty acids. These findings indicate that 14-3-3β and γ are novel PPARγ₂ regulators and are involved in hepatic lipid metabolism. 14-3-3β and γ can be therapeutic target molecules to treat non-alcoholic fatty liver disease.